Third Gene Tied to Early Onset Alzheimer's

Published: August 18, 1995

WASHINGTON, Aug. 17—
A gene mutation found among a small group with German-Russian ancestry has been identified as the third to cause early onset Alzheimer's disease. Scientists say the discovery may speed the development of drugs to combat the disorder.

Researchers isolated the gene by probing the chromosomes of a group that has a very high incidence of Alzheimer's before the age of 65. The affected group is a small subset of the Volga Germans, descendants of the Germans who migrated to the Volga River area of Russia in the 18th century and moved to the United States in this century.

The mutated gene is found on chromosome 1 of the 23 pairs of chromosomes in human cells and has been directly linked to Alzheimer's. Two reports on the discovery will be published on Friday in the journal Science.

People who inherit one of the three rare gene mutations for early onset Alzheimer's develop the disease before the age of 65; sometimes they are as young as 40 when they become ill.

Dr. Rudolph E. Tanzi of Massachusetts General Hospital, a principal collaborator in the research, said the new Alzheimer's gene was responsible for a protein that is closely related to an Alzheimer's protein linked to a chromosome-14 gene found by Dr. Tanzi's team.

This similarity, Dr. Tanzi said, puts researchers on a fast track for understanding the cause of beta amyloid, a gluelike substance that is toxic to brain cells and is a primary feature of Alzheimer's.

He said the two proteins might have common functions even though they are produced from different genes. Once the function of these proteins is found, Dr. Tanzi said, researchers can develop a drug to block the disease.

"This is an incredibly important discovery," said Dr. Marcelle Morrison-Bogorad, a professor of neurology at the University of Texas Southwestern Medical School in Dallas. "This means that genetics has pretty much solved the mystery of early-onset" Alzheimer's disease, Dr. Morrison-Bogorod said. "It clears a path for scientific research that wasn't there before."

With three genes identified for early onset Alzheimer's, she said, researchers can focus on the molecular processes associated with the genes. "The body makes about 100,000 proteins," Dr. Morrison-Bogorad said. "Now, instead of having to study 100,000, we can concentrate on the three proteins" made by these genes.

In 1987, Dr. Tanzi and his team found the first Alzheimer's gene, on chromosome 21. In June, they isolated the chromosome-14 gene.

Alzheimer's is a progressive disorder that slowly disables the brain. It first erodes the memory and progressively wipes out other brain functions, until death ensues.

About four million Americans have Alzheimer's. It is the fourth-leading cause of death, killing about 100,000 people annually. More than 90 percent of Alzheimer's patients develop the disease after the age of 65, and some studies suggest that about half of everyone over the age of 85 is afflicted.

To find the early onset Alzheimer's genes, researchers analyzed the genes of family groups in which Alzheimer's occurred in generation after generation at early ages.

The chromosome-1 gene was tracked down when scientists led by Dr. Gerard D. Schellenberg of the Veterans Affairs Medical Center in Seattle studied the genetic makeup of the Volga German group.

Dr. Schellenberg's team determined that those families had a gene defect somewhere on chromosome 1. About the same time, Dr. Tanzi and his group found evidence of an unidentified gene that was similar to the Alzheimer's gene they had found earlier on chromosome 14.

Dr. Tanzi and Dr. Schellenberg pooled their early findings, which speeded the research. Within days of each other, the two teams isolated the Alzheimer's gene mutation on chromosome 1.

About 70 percent of early onset Alzheimer's patients are in families with the chromosome-14 defect, Dr. Tanzi said. The chromosome-1 defect is thought to account for about 25 percent of such cases, and the chromosome-21 flaw for about 5 percent.